Buccal, polar and non-polar spray or capsule

ABSTRACT

Buccal aerosol sprays or capsule using polar and non-polar solvent have now been developed which provide biologically active compounds for rapid absorption through the oral mucosa, resulting in fast onset of effect. The buccal polar compositions of the invention comprises formulation I: polar solvent 37-98.58%, active compound 0.005-55%, optionally containing flavoring agent 0.1-10%.

RELATED APPLICATIONS

This patent application is a division of U.S. Utility Patent ApplicationSer. No. 09/537,118, filed on Mar. 29, 2000, which is a continuation inpart of applicant PCT application PCT/US97/17899 filed Oct. 1, 1997.

BACKGROUND OF THE INVENTION

It is known that certain biologically active compounds are betterabsorbed through the oral mucosa than through other routes ofadministration, such as through the stomach or intestine. However,formulations suitable for such administration by these latter routespresent their own problems. For example, the biologically activecompound must be compatible with the other components of the compositionsuch as propellants, solvents, etc. Many such formulations have beenproposed. For example, U.S. Pat. No. 4,689,233, Dvorsky et al.,describes a soft gelatin capsule for the administration of theanti-coronary drug nifedipine dissolved in a mixture of polyetheralcohols. U.S. Pat. No. 4,755,389, Jones et al., describes a hardgelatin chewable capsule containing nifedipine. A chewable gelatincapsule containing a solution or dispersion of a drug is described inU.S. Pat. No. 4,935,243, Borkan et al. U.S. Pat. No. 4,919,919, Aouda etal, and U.S. Pat. No. 5,370,862, Klokkers-Bethke, describe anitroglycerin spray for administration to the oral mucosa comprisingnitroglycerin, ethanol, and other components. An orally administeredpump spray is described by Cholcha in U.S. Pat. No. 5,186,925. Aerosolcompositions containing a hydrocarbon propellant and a drug foradministration to a mucosal surface are described in U.K. 2,082,457, Su,U.S. Pat. No. 3,155,574, Silson et al., U.S. Pat. No. 5,011,678, Wang etal., and by Parnell in U.S. Pat. No. 5,128,132. It should be noted thatthese references discuss bioavailability of solutions by inhalationrather than through the membranes to which they are administered.

SUMMARY OF THE INVENTION

A buccal aerosol spray or soft bite gelatin capsule using a polar ornon-polar solvent has now been developed which provides biologicallyactive compounds for rapid absorption through the oral mucosa, resultingin fast onset of effect.

The buccal aerosol spray compositions of the present invention, fortransmucosal administration of a pharmacologically active compoundsoluble in a pharmacologically acceptable non-polar solvent comprise inweight % of total composition: pharmaceutically acceptable propellant5-80%, non-polar solvent 20-85%, active compound 0.05-50%, suitablyadditionally comprising, by weight of total composition a flavoringagent 0.01-10%. Preferably the composition comprises: propellant 10-85%,non-polar solvent 25-89.9%, active compound 0.01-40%, flavoring agent1-8%; most suitably propellant 20-70%, non-polar solvent 30-74.75%,active compound 0.25-35%, flavoring agent 2-7.5%.

The buccal polar aerosol spray compositions of the present invention,for transmucosal administration of a pharmacologically active compoundsoluble in a pharmacologically acceptable polar solvent are alsoadministrable in aerosol form driven by a propellant. In this case thecomposition comprise in weight % of total composition: aqueous polarsolvent 10-99%, active compound 0.1-25%, suitably additionallycomprising, by weight of total composition a flavoring agent 0.05-10%and propellant: 2-10%. Preferably the composition comprises: polarsolvent 20-97%, active compound 0.1-15%, flavoring agent 0.1-5% andpropellant: 3-5%; most suitably polar solvent 25-97%, active compound0.2-25%, flavoring agent 0.1-2.5% and propellant: 3-4%.

The buccal pump spray composition of the present invention fortransmucosal administration of a pharmacologically active compound wheresaid active compound is soluble in a pharmacologically acceptablenon-polar solvent said composition comprise in weight % of totalcomposition: non-polar solvent 30-99.69%, active compound 0.005-55%, andsuitably additionally, flavoring agent 0.1-10%.

The buccal polar pump spray compositions of the present invention, fortransmucosal administration of a pharmacologically active compoundsoluble in a pharmacologically acceptable polar solvent comprising inweight % of total composition: aqueous polar solvent 30-99.69%, activecompound 0.001-60%, suitably additionally comprising, by weight of totalcomposition a flavoring agent 0.1-10%. Preferably the compositioncomprises: polar solvent 37-98.58%, active compound 0.005-55%, flavoringagent 0.5-8%; most suitably polar solvent 60.9-97.06%, active compound0.01-40%, flavoring agent 0.75-7.5%.

The soft bite gelatin capsules of the present invention for transmucosaladministration of a pharmacologically active compound, at leastpartially soluble in a pharmacologically acceptable non-polar solvent,having charged thereto a fill composition comprise in weight % of totalcomposition: non-polar solvent 4-99.99%, emulsifier 0-20%, activecompound 0.01-80%, provided that said fill composition contains lessthan 10% of water, suitably additionally comprising, by weight of thecomposition: flavoring agent 0.01-10%. Preferably, the soft bite gelatincapsule comprises: non-polar solvent 21.5-99.975%, emulsifier 0-15%,active compound 0.025-70%, flavoring agent 1-8%; most suitably:non-polar solvent 28.5-97.9%, emulsifier 0-10%, active compound0.1-65.0%, flavoring agent 2-6%.

The soft bite polar gelatin capsules of the present invention fortransmucosal administration of a pharmacologically active compound, atleast partially soluble in a pharmacologically acceptable polar solvent,having charged thereto a composition comprising in weight % of totalcomposition: polar solvent 25-99.89%, emulsifier 0-20%, active compound0.01-65%, provided that said composition contains less than 10% ofwater, suitably additionally comprising, by weight of the composition:flavoring agent 01-10%. Preferably, the soft bite gelatin capsulecomprises: polar solvent 37-99.95%, emulsifier 0-15%, active compound0.025-55%, flavoring agent 1-8%; most suitably: polar solvent44-96.925%, emulsifier 0-10%, active compound 0.075-50%, flavoring agent2-6%.

It is an object of the invention to coat the mucosal membranes eitherwith extremely fine droplets of spray containing the active compounds ora solution or paste thereof from bite capsules.

It is also an object of the invention to administer to the oral mucosaof a mammalian in need of same, preferably man, by spray or bitecapsule. a predetermined amount of a biologically active compound bythis method or from a soft gelatin bite capsule.

A further object is a sealed aerosol spray container containing acomposition of the non polar or polar aerosol spray formulation, and ametered valve suitable for releasing from said container a predeterminedamount of said composition.

As the propellant evaporates after activation of the aerosol valve, amist of fine droplets is formed which contains solvent and activecompound.

The propellant is a non-Freon material, preferably a C₃₋₈ hydrocarbon ofa linear or branched configuration. The propellant should besubstantially non-aqueous. The propellant produces a pressure in theaerosol container such that under expected normal usage it will producesufficient pressure to expel the solvent from the container when thevalve is activated but not excessive pressure such as to damage thecontainer or valve seals.

The non-polar solvent is a non-polar hydrocarbon, preferably a C₇₋₁₈hydrocarbon of a linear or branched configuration, fatty acid esters,and triglycerides, such as miglyol. The solvent must dissolve the activecompound and be miscible with the propellant, i.e., solvent andpropellant must form a single phase at 0-4° C. at a pressure range of1-3 atm.

The polar and non-polar aerosol spray compositions of the invention areintended to be administered from a sealed, pressurized container. Unlikea pump spray, which allows the entry of air into the container afterevery activation, the aerosol container of the invention is sealed atthe time of manufacture. The contents of the container are released byactivation of a metered valve, will does not allow entry of atmosphericgasses with each activation. Such containers are commercially available.

A further object is a pump spray container containing a composition ofthe pump spray formulation, and a metered valve suitable for releasingfrom said container a predetermined amount of said composition.

A further object is a soft gelatin bite capsule containing a compositionof as set forth above. The formulation may be in the form of a viscoussolution or paste containing the active compounds. Although solutionsare preferred, paste fills may also be used where the active compound isnot soluble or only partially soluble in the solvent of choice. Wherewater is used to form part of the paste composition, it should notexceed 10% thereof. (All percentages herein are by weight unlessotherwise indicated.)

The polar or non-polar solvent is-chosen such that it is compatible withthe gelatin shell and the active compound. The solvent preferablydissolves the active compound. However, other components wherein theactive compound is not soluble or only slightly soluble may be used andwill form a paste fill.

Soft gelatin capsules are well known in the art. See, for example, U.S.Pat. No. 4,935,243, Borkan et al., for its teaching of such capsules.The capsules of the present invention are intended to be bitten into torelease the low viscosity solution or paste therein, which will thencoat the buccal mucosa with the active compounds. Typical capsules,which are swallowed whole or bitten and then swallowed, deliver theactive compounds the stomach, which results in significant lag timebefore maximum blood levels can be achieved or subject the compound to alarge first pass effect. Because of the enhanced absorption of thecompounds through the oral mucosa and no chance of a first pass effect,use of the bite capsules of the invention will eliminate much of the lagtime, resulting in hastened onset of biological effect. The shell of asoft gelatin capsule of the invention may comprise, for example:

Gelatin: 50-75%, glycerin 20-30%, colorants 0.5-1.5%, water 5-10%, andsorbitol 2-10%.

The active compound may include biologically active peptides, centralnervous system active amines, sulfonyl ureas, antibiotics, antifungals,antivirals, sleep inducers, antiasthmatics, bronchial dilators,antiemetics, histamine H-2 receptor antagonists, barbiturates,prostaglandins and neutraceuticals.

The active compounds may also include antihistamines, alkaloids,hormones, benzodiazepines and narcotic analgesics. While not limitedthereto, these active compounds are particularly suitable for non-polarpump spray formulation and application.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE is a schematic diagram showing routes of absorption andprocessing of pharmacologically active substances in a mammalian system.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The preferred active compounds of the present invention are in anionized, salt form or as the free base of the pharmaceuticallyacceptable salts thereof (provided, for the aerosol or spraycompositions, they are soluble in the spray solvent). These compoundsare soluble in the non-polar solvents of the invention at usefulconcentrations or can be prepared as pastes at useful concentrations.These concentrations may be less than the standard accepted dose forthese compounds since there is enhanced absorption of the compoundsthrough the oral mucosa. This aspect of the invention is especiallyimportant when there is a large (40-99.99%) First pass effect.

As propellants for the non polar sprays, propane, N-butane, iso-butane,N-pentane, iso-pentane, and neo-pentane, and mixtures thereof may beused. N-butane and iso-butane, as single gases, are the preferredpropellants. It is permissible for the propellant to have a watercontent of no more than 0.2%, typically 0.1-0.2%. (All percentagesherein are by weight unless otherwise indicated.) It is also preferablethat the propellant be synthetically produced to minimize the presenceof contaminants which are harmful to the active compounds. Thesecontaminants include oxidizing agents, reducing agents, Lewis acids orbases, and water. The concentration of each of these should be less than0.1%, except that water may be as high as 0.2%.

Suitable non-polar solvents for the capsules and the non-polar spraysinclude (C₂-C₂₄) fatty acid C₂-C₆ esters, C₇-C₁₈ hydrocarbon, C₂-C₆alkanoyl esters, and the triglycerides of the corresponding acids. Whenthe capsule fill is a paste, other liquid components may be used insteadof the above low molecular weight solvents. These include soya oil, cornoil, other vegetable oils.

As solvents for the polar capsules or sprays there may be used lowmolecular weight polyethyleneglycols (PEG) of 400-1000 Mw (preferably400-600), low molecular weight (C₂-C₈) mono and polyols and alcohols ofC₇-C₁₈ linear or branch chain hydrocarbons, glycerin may also be presentand water may also be used in the sprays, but only in limited amount inthe capsules.

It is expected that some glycerin and water used to make the gelatinshell will migrate from the shell to the fill during the curing of theshell. Likewise, there may be some migration of components from the fillto the shell during curing and even throughout the shelf-life of thecapsule. Therefore, the values given herein are for the compositions asprepared, it being within the scope of the invention that minorvariations will occur.

The preferred flavoring agents are synthetic or natural oil ofpepper-mint, oil of spearmint, citrus oil, fruit flavors, sweeteners(sugars, aspartame, saccharin, etc.), and combinations thereof.

The active substances include the active compounds selected from thegroup consisting of cyclosporine, sermorelin, Octreotide acetate,calcitonin-salmon, insulin lispro, sumatriptan succinate, clozepine,cyclobenzaprine, dexfenfluramine hydrochloride, glyburide, zidovudine,erythromycin, ciprofloxacin, ondansetron hydrochloride, dimenhydrinate,cimetidine hydrochloride, famotidine, phenytoin sodium, phenytoin,carboprost thromethamine, carboprost, diphenhydramine hydrochloride,isoproterenol hydrochloride, terbutaline sulfate, terbutaline,theophylline, albuterol sulfate and neutraceuticals, that is to saynutrients with pharmacological action such as but not limited tocarnitine, valerian, echinacea, and the like.

The formulations of the present invention comprise an active compound ora pharmaceutically acceptable salt thereof. The term “pharmaceuticallyacceptable salts” refers to salts prepared from pharmaceuticallyacceptable non-toxic acids or bases including organic and inorganicacids or bases.

When an active compound of the present invention is acidic, salts may beprepared from pharmaceutically acceptable non-toxic bases. Salts derivedfrom all stable forms of inorganic bases include aluminum, ammonium,calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium,zinc, etc. Particularly preferred are the ammonium, calcium, magnesium,potassium, and sodium salts. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion-exchange resins such asarginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethyl-aminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethyl-piperidine,glucamine, glucosamine, histidine, isopropylamine, lysine,methyl-glucosamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purine, theobromine, triethylamine, trimethylamine,tripropylamine, etc.

When an active compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethane-sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, mandelic, methanesulfonic, mucic, nitric,pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic, etc. Particularly preferred are citric, hydrobromic,maleic, phosphoric, sulfuric, and tartaric acids.

In the discussion of methods of treatment herein, reference to theactive compounds is meant to also include the pharmaceuticallyacceptable salts thereof. While certain formulations are set forthherein, the actual amounts to be administered to the mammal or man inneed of same are to be determined by the treating physician.

The invention is further defined by reference to the following examples,which are intended to be illustrative and not limiting.

The following are examples of each class (all values unless otherwisespecified are in weight percent):

EXAMPLE 1

Biologically active peptides including peptide hormones most preferredpreferred Amounts amount amount A. Cyclosporine lingual sprayCyclosporine  5-50 10-35 15-25 water  5-20 7.5-50  9.5-12  ethanol  5-607.5-50  10-20 polyethylene glycol 20-60 30-45 35-40 flavors 0.1-5   1-42-3 B. Cyclosporine Non-Polar lingual spray Cyclosporine  1-50  3-40 5-30 Migylol  ®* 30-40 Polyoxyethyl- 30-40 ated castor oil Butane 25-8030-70 33-50 flavors 0.1-5   1-4 2-3 C. Cyclosporine non-polar bitecapsule Cyclosporine  1-35  5-25 10-20 olive oil 25-60 35-55 30-45polyoxyethyl- 25-60 35-55 30-45 ated oleic glycerides flavors 0.1-5  1-4 2-3 D. Cyclosporine bite capsule Cyclosporine  5-50 10-35 15-25polyethylene glycol 20-60 30-45 35-40 glycerin  5-30 7.5-25  10-20propylene glycol  5-30 7.5-25  10-20 flavors 0.1-10  1-8 3-6 E.Sermorelin (as the acetate) lingual spray sermorelin (as the .01-5  .1-3   .2-1.0 acetate) mannitol,  1-25  5-20 10-15 monobasic sodium0.1-5   1-3 1.5-2.5 phosphate, dibasic sodium 0.01-5   .05-3  0.1-0.5phosphate water ethanol  5-30 7.5-25  9.5-15  polyethylene glycol 20-6030-45 35-40 propylene glycol  5-25 10-20 12-17 flavors 0.1-5   1-4 2-3F. Octreotide acetate (Sandostatin*) lingual spray octreotide acetate0.001-0.5  0.005-0.250 0.01-0.10 acetic acid  1-10 2-8 4-6 sodiumacetate  1-10 2-8 4-6 sodium chloride  3-30  5-25 15-20 flavors 0.1-5  0.5-.4  2-3 ethanol  5-30 7.5-20  9.5-15  water 15-95 35-90 65-85flavors 0.1-5   1-4 2-3 G. Calcitonin-salmon lingual sprayCalcitonin-salmon 0.001-5    0.005-2     01-1.5 ethanol  2-15  3-10  7-9.5 water 30-95 50-90 60-80 polyethylene glycol  2-15  3-10   7-9.5sodium chloride 2.5-20   5-15   10-12.5 flavors 0.1-5   1-4 2-3 H.insulin lispro, lingual spray insulin, 20-60  4-55  5-50 glycerin,0.1-10  0.25-5   0.1-1.5 dibasic sodium  1-15 2.5-10  4-8 phosphate,m-cresol,  1-25  5-25  7.5-12.5 zinc oxide 0.01-0.25  .05-0.150.075-0.10  m-cresol, 0.1-1   0.2-0.8 0.4-0.6 phenol trace amounts traceamounts trace amounts ethanol  5-20 7.5-15   9-12 water 30-90 40-8050-75 propylene glycol  5-20 7.5-15   9-12 flavors 0.1-5   0.5-3  0.75-2   adjust pH to 7.0-7.8 with HCl or NaOH *Miglyol is a registeredtrademark of Hules AG and describes a fractionated coconut oil ofboiling point 240-270° C. comprising saturated C₈ and C₁₀ triglycerides.

EXAMPLE 2

CNS active amines and their salts: including but not limited totricyclic amines, GABA analogues, thiazides, phenothiazine derivatives,Serotonin antagonists and serotonin reuptake inhibitors most preferredpreferred Amounts amount amount A. Sumatriptan succinate lingual spraysumatriptan succinate 0.5-30   1-20 10-15 ethanol  5-60 7.5-50  10-20propylene glycol  5-30 7.5-20  10-15 polyethylene glycol  0-60 30-4535-40 water  5-30 7.5-20  10-15 flavors 0.1-5   1-4 2-3 B. Sumatriptansuccinate bite capsule sumatriptan succinate 0.01-5   0.05-3.5 0.075-1.75  polyethylene glycol 25-70 30-60 35-50 glycerin 25-70 30-6035-50 flavors 0.1-10  1-8 3-6 C. Clozepine lingual spray Clozepine0.5-30   1-20 10-15 ethanol  5-60 7.5-50  10-20 propylene glycol  5-307.5-20  10-15 polyethylene glycol  0-60 30-45 35-40 water  5-30 7.5-20 10-15 flavors 0.1-5   1-4 2-3 D. Clozepine Non-Polar lingual spray withpropellant Clozepine 0.5-30   1-20 10-15 Migylol 20-85 25-70 30-40Butane 15-80 30-75 60-70 flavors 0.1-5   1-4 2-3 E. Clozepine Non-Polarlingual spray without propellant Clozepine 0.5-30   1-20 10-15 Migylol  70-99.5 80-99 85-90 flavors 0.1-5   1-4 2-3 F. Cyclobenzaprine Nonpolar lingual spray Cyclobenzaprine 0.5-30   1-20 10-15 (base) Migylol20-85 25-70 30-40 Iso-butane 15-80 30-75 60-70 flavors 0.1-5   1-4 2-3G. dexfenfluramine hydrochloride lingual spray dexfenfluramine Hcl  5-307.5-20  10-15 ethanol  5-60 7.5-50  10-20 propylene glycol  5-30 7.5-20 10-15 polyethylene glycol  0-60 30-45 35-40 water  5-30 7.5-20  10-15flavors 0.1-5   1-4 2-3

EXAMPLE 3

Sulfonylureas most preferred preferred Amount amount amount A. Glyburidelingual spray Glyburide 0.25-25   0.5-20  0.75-15   ethanol 5-60 7.5-50 10-20 propylene glycol 5-30 7.5-20  10-15 polyehtylene glycol 0-60 30-4535-40 water 2.5-30    5-20  6-15 flavors 0.1-5   1-4 2-3 B. Glyburidenon-polar bite capsule Glyburide 0.01-10   0.025-7.5  0.1-4   olive oil30-60 35-55 30-50 polyoxyethyl- 30-60 35-55 30-50 ated oleic glyceridesflavors 0.1-5   1-4 2-3

EXAMPLE 4

Antibiotics anti-fungals and anti-virals most preferred preferredAmounts amount amount A. zidovudine [formerly called azidothymidine(AZT) (Retrovir) non-polar lingual spray zidovudine 10-50 15-40 25-35Soya oil 20-85 25-70 30-40 Butane 15-80 30-75 60-70 flavors 0.1-5   1-42-3 B. Erythromycin bite capsule bite capsule Erythromycin 25-65 30-5035-45 polyoxyethylene glycol  5-70 30-60 45-55 glycerin  5-20 7.5-15   10-12.5 flavors  1-10 2-8 3-6 C. Ciprofloxacin hydrochloride bitecapsule Ciprofloxacin hydrochloride 25-65 35-55 40-50 glycerin  5-207.5-15    10-12.5 polyethylene glycol 20-75 30-65 40-60 flavors  1-102-8 3-6 D. zidovudine [formerly called azidothymidine (AZT) (Retrovir)lingual spray zidovudine 10-50 15-40 25-35 water 30-80 40-75 45-70ethanol  5-20 7.5-15   9.5-12.5 polyethylene glycol  5-20 7.5-15  9.5-12.5 flavors 0.1-5   1-4 2-3

EXAMPLE 5

Anti-emetics most preferred preferred Amounts amount amount A.Ondansetron hydrochloride lingual spray ondansetron hydrochloride  1-25 2-20 2.5-15  citric acid monohydrate,  1-10 2-8 2.5-5   sodium citratedihydrate 0.5-5   1-4 1.25-2.5  water  1-90  5-85 10-75 ethanol  5-307.5-20  9.5-15  propylene glycol  5-30 7.5-20  9.5-15  polyethyleneglycol  5-30 7.5-20  9.5-15  flavors  1-10 3-8   5-7.5 B. Dimenhydrinatebite capsule Dimenhydrinate 0.5-30   2-25  3-15 glycerin  5-20 7.5-15   10-12.5 polyethylene glycol 45-95 50-90 55-85 flavors  1-10 2-8 3-6 C.Dimenhydrinate polar lingual spray Dimenhydrinate  3-50  4-40  5-35water  5-90 10-80 15-75 ethanol  1-80  3-50  5-10 polyethylene  1-80 3-50  5-15 glycol Sorbitol 0.1-5   0.2-4   0.4-1.0 aspartame 0.01-0.5 0.02-0.4  0.04-0.1  flavors 0.1-5   1-4 2-3

EXAMPLE 6

Histamine H-2 receptor antagonists most preferred preferred Amountsamount amount A. Cimetidine hydrochloride bite capsule Cimetidine Hcl10-60 15-55 25-50 glycerin  5-20 7.5-15    10-12.5 polyethylene glycol20-90 25-85 30-75 flavors  1-10 2-8 3-6 B. Famotidine lingual sprayFamotidine  1-35  5-30  7-20 water 2.5-25   3-20  5-10 L-aspartic acid0.1-20   1-15  5-10 polyethylene glycol 20-97 30-95 50-85 flavors0.1-10    1-7.5 2-5 C. Famotidine non-polar lingual spray Famotidine 1-35  5-30  7-20 Soya oil 10-50 15-40 15-20 Butane 15-80 30-75 45-70polyoxyethyl- 10-50 15-40 15-20 ated oleic glycerides flavors 0.1-5  1-4 2-3

EXAMPLE 7

Barbiturates most preferred preferred Amounts amount amount A. Phenytoinsodium lingual spray Phenytoin sodium 10-60 15-55 20-40 water 2.5-25  3-20  5-10 ethanol  5-30 7.5-20  9.5-15  propylene glycol  5-30 7.5-20 9.5-15  polyethylene glycol  5-30 7.5-20  9.5-15  flavors  1-10 3-8  5-7.5 B. Phenytoin non-polar lingual spray Phenytoin  5-45 10-40 15-35migylol 10-50 15-40 15-20 Butane 15-80 30-75 60-70 polyoxyethyl- 10-5015-40 15-20 ated oleic glycerides flavors 0.1-10  1-8   5-7.5

EXAMPLE 8

Prostaglandins most preferred preferred Amounts amount amount A.Carboprost thromethamine lingual spray Carboprost thromethamine 0.05-5  0.1-3   0.25-2.5  water 50-95 60-80 65-75 ethanol  5-20 7.5-15  9.5-12.5 polyethylene glycol  5-20 7.5-15   9.5-12.5 sodium chloride 1-20  3-15 4-8 flavors 0.1-5   1-4 2-3 pH is adjusted with sodiumhydroxide and/or hydrochloric acid B. Carboprost non-polar lingual sprayCarboprost 0.05-5   0.1-3   0.25-2.5  migylol 25-50 30-45 35-40 Butane 5-60 10-50 20-35 polyoxyethyl- 25-50 30-45 35-40 ated oleic glyceridesflavors 0.1-10  1-8   5-7.5

EXAMPLE 9

Neutraceuticals most preferred preferred Amounts amount amount A.Carnitine as bite capsule (contents are a paste) Carnitine fumarate 6-80 30-70 45-65 soya oil 7.5-50  10-40 12.5-35   soya lecithin0.001-1.0  0.005-0.5  .01-0.1 Soya fats 7.5-50  10-40 12.5-35   flavors 1-10 2-8 3-6 B. Valerian as lingual spray Valerian extract 0.1-10 0.2-7   0.25-5   water 50-95 60-80 65-75 ethanol  5-20 7.5-15   9.5-12.5polyethylene glycol  5-20 7.5-15   9.5-12.5 flavors  1-10 2-8 3-6 B.Echinacea as bite capsule Echinacea extract 30-85 40-75 45-55 soya oil7.5-50  10-40 12.5-35   soya lecithin 0.001-1.0  0.005-0.5  .01-0.1 Soyafats 7.5-50  10-40 12.5-35   flavors  1-10 2-8 3-6 B. Mixtures ofingredients Magnesium oxide 15-40 20-35 25-30 Chromium picolinate0.01-1.0  0.02-0.5  .025-0.75 folic acid .025-3.0  0.05-2.0  0.25-0.5 vitamin B-12 0.01-1.0  0.02-0.5  .025-0.75 vitamin E 15-40 20-35 25-30Soya oil 10-40 12.5-35   15-20 soya lecithin 0.1-5   0.2-4   0.5-1.5soya fat 10-40 15-35 17.5-20  

EXAMPLE 10

Sleep Inducers (also CNS active amine) most preferred preferred Amountsamount amount A. Diphenhydramine hydrochloride lingual sprayDiphenhydramine  3-50  4-40  5-35 Hcl water  5-90 10-80 50-75 ethanol 1-80  3-50  5-10 polyethylene  1-80  3-50  5-15 glycol Sorbitol 0.1-5  0.2-4   0.4-1.0 aspartame 0.01-0.5  0.02-0.4  0.04-0.1  flavors 0.1-5  1-4 2-3

EXAMPLE 11

Anti-Asthmatics-Bronchodilators most preferred preferred Amounts amountamount A. Isoproterenol Hydrochloride as polar lingual sprayIsoproterenol 0.1-10  0.2-7.5 0.5-6   Hydrochloride water  5-90 10-8050-75 ethanol  1-80  3-50  5-10 polyethylene  1-80  3-50  5-15 glycolSorbitol 0.1-5   0.2-4   0.4-1.0 aspartame 0.01-0.5  0.02-0.4  0.04-0.1 flavors 0.1-5   1-4 2-3 B. Terbutaline sulfate as polar lingual sprayTerbutaline 0.1-10  0.2-7.5 0.5-6   sulfate water  5-90 10-80 50-75ethanol  1-10 2-8 2.5-5   Sorbitol 0.1-5   0.2-4   0.4-1.0 aspartame0.01-0.5  0.02-0.4  0.04-0.1  flavors 0.1-5   1-4 2-3 C. Terbutaline asnon-polar lingual spray Terbutaline 0.1-10  0.2-7.5 0.5-6   migylol25-50 30-45 35-40 isobutane  5-60 10-50 20-35 polyoxyethylated 25-5030-45 35-40 oleic glycerides flavors 0.1-10  1-8   5-7.5 D. Theophyllinepolar bite capsule Theophylline  5-50 10-40 15-30 polyethylene 20-6025-50 30-40 glycol glycerin 25-50 35-45 30-40 propylene glycol 25-5035-45 30-40 flavors 0.1-5   1-4 2-3 E. Albuterol sulfate as polarlingual spray Albuterol sulfate 0.1-10  0.2-7.5 0.5-6   water  5-9010-80 50-75 ethanol  1-10 2-8 2.5-5   Sorbitol 0.1-5   0.2-4   0.4-1.0aspartame 0.01-0.5  0.02-0.4  0.04-0.1  flavors 0.1-5   1-4 2-3

EXAMPLE 12

Polar solvent formulations using a propellant: Most- Preferred PreferredAmount Amount Amount A. Sulfonylurea Glyburide 0.1-25%   0.5-15%  0.6-10%  Ethanol 40-99%  60-97%  70-97% Water 0.01-5%    0.1-4%  0.2-2%   Flavors 0.05-10%   0.1-5%   0.1-2.5% Propellant 2-10% 3-5% 3-4% B. Prostaglandin E₁ (vasodilator) Prostaglandin E₁ 0.01-10%  0.1-5%   0.2-3%   Ethanol 10-90%  20-75%  25-50% Propylene glycol 1-90%5-80% 10-75% Water 0.01-5%    0.1-4%   0.2-2%   Flavors 0.05-10%  0.1-5%   0.1-2.5% Propellant 2-10% 3-5%  3-4% C. Promethazine(antiemetic, sleep inducer, and CNS active amine) Promethazine 1-25%3-15%  5-12% Ethanol 10-90%  20-75%  25-50% Propylene glycol 1-90% 5-80%10-75% Water 0.01-5%    0.1-4%   0.2-2%   Flavors 0.05-10%   0.1-5%  0.1-2.5% Propellant 2-10% 3-5%  3-4% D. Meclizine Meclizine 1-25% 3-15% 5-12% Ethanol 1-15% 2-10% 3-6% Propylene glycol 20-98%  5-90% 10-85%Water 0.01-5%    0.1-4%   0.2-2%   Flavors 0.05-10%   0.1-5%   0.1-2.5%Propellant 2-10% 3-5%  3-4%

What is claimed is:
 1. A propellant free pump spray compositioncomprising a pharmacologically acceptable polar solvent in an amount of75-85 weight percent of the total composition, cyclosporin in an amountof 15-25 weight percent of the total composition, and flavoring agent inan amount of 0.1-5 weight percent of the total composition wherein saidcomposition is adapted for transmucosal administration of thecyclosporin through the oral mucosa.
 2. A propellant free pump spraycomposition comprising a pharmacologically acceptable polar solvent inan amount of 19-90 weight percent of the total composition, ondansetronhydrochloride in an amount of 2.5-15 weight percent of the totalcomposition, and flavoring agent in an amount of 0.1-10 weight percentof the total composition wherein said composition is adapted fortransmucosal administration of the ondansetron hydrochloride through theoral mucosa.